1. Field of the Invention
This invention relates to the use of an intravascular artificial organ to deliver hormones and other biologically producible substances to the human body for the treatment of endocrine (secretory) organ failure and other conditions.
2. Information Disclosure Statement
One example of endocrine organ failure which this device can treat is diabetes.
Diabetes results when the pancreas is not able to secrete enough of the hormone insulin. Insulin regulates the metabolism of glucose in the body. Failure of the pancreas to produce insulin in sufficient quantities results in the accumulation of high levels of glucose in the blood after oral intake of foods containing glucose. For reasons which are not yet understood, this causes injury to the blood vessels of the eye, kidneys, and other tissues of the body. Blindness, kidney failure, and amputation are among the sequelae of diabetes.
Once it was recognised that diabetes was caused by insufficient insulin levels, it became possible to treat diabetes by giving insulin injections. It was learned that the insulin molecule produced by both pigs and cows was effective in humans. Insulin extracted from the pancreatic issue of these animals was injected into the bodies of diabetics several times each day. This method of treatment prevented the death of thousands of people with diabetes. It was soon recognised that frequent injections of insulin were difficult to maintain for a lifetime. The insulin molecule was therefore combined with other elements such as zinc to prolong its action. This enabled treatment by injections once or twice daily in many patients. A number of problems remained. First, it was only possible to estimate the average insulin requirement. Increased dietary intake resulted in abnormally high blood glucose levels. Alternatively, blood glucose would be abnormally low if meals were skipped. Some patients were unable to manage their strict dietary requirements and insulin injection schedules. Many of these patients succumbed to their disease. Others suffered the complications of diabetes mentioned above.
It has long been recognized that restoring normal pancreatic endocrine function to diabetics would be a dramatic breakthrough in the treatment of this disease. There have been several approaches to this end.
First, transplantation of human or animal pancreatic tissue or islet cells into diabetics has been attempted by many groups. (See Sutherland, et al., Transplantation Proceedings, 19:291-297(181); Sutherland, Diabetologia, 20:161-185(1981); Naji, Surgery, 86:218-224(1979)). There are several problems with this approach. The most significant of these problems is that the transplanted tissue is recognized as foreign by the immune system of the recipient. This foreign tissue is then destroyed by the recipient's body. Attempts to suppress the immune system of the recipient are complicated by increased susceptibility to infection and cancer. A second problem is caused by other materials secreted by pancreatic tissue. In addition to insulin, the pancreas produces enzyme which aid in the digestion of meat. Transplanted pancreatic tissue secretes these enzymes, which then interfere with healing after the transplant operation.
Second, mechanical pumping devices of various design have been used to deliver insulin to diabetics on a continuous basis. One of the major problems with this approach is that the pump must deliver insulin at a rate proportional to the glucose in the blood. Continuous measurement of blood glucose and feedback to the pumping device have proven to be a major stumbling block. In addition, mechanical devices require an energy supply and are prone to failure. A practical mechanical pancreas substitute does not exist at this time.
The third approach has been to enclose pancreatic tissue from other people or animals in a semipermeable enclosure. By selecting a material with a pore size of approximately 50,000 Daltons, it is possible for oxygen and glucose to diffuse into the foreign tissue. The tissue produces insulin in quantities proportional to the concentration of glucose present. This insulin then diffuses out of the enclosure and throughout the rest of the body. Although oxygen, glucose, and insulin can flow through the pores, cells and immunoglobulins of the recipient immune system cannot. Thus, the pancreatic tissue is protected from the host's immune system.
This system has bee used to restore normal glucose metabolism to diabetic rats. Pancreatic tissue was enzymatically digested, and the insulin-secreting units called islets extracted and concentrated. The islets were then loaded into capillary tubes made of a suitable semipermeable polymer, and these capillaries were implanted in the peritoneal cavity of rats previously made diabetic by treatment with streptozocin (a pancreatic poison). Approximately half of the animals so treated demonstrated normal glucose metabolism one year later. (Altman, et al., Diabetes, 35:625(June 1986)).
Attempts to adapt this technique to larger animals have been based on construction of an implantable chamber containing pancreatic islets in a suitable growth medium. This chamber contains a conduit constructed of suitable semipermeable membrane. The resulting device is then connected between an artery and a vein, resulting in blood flow through the device. (Tze, et al., Diabetologia, 19:541(1980); Sun, et al., in BIOCOMPATIBLE POLYMERS SCIENCE AND TECHNOLOGY, Chap. 40, p 929 Szycher, ed.;1983)). These devices have been proven impractical because blood flowing through the devices tends to clot, thus rendering them useless.
Jordan, U.S. Pat. No. 3,093,831 describes a primitive artificial gland comprising a semipermeable bag holding glandular tissue. The bag is tied closed, and its pores have a molecular weight cutoff of no more than 10,000-15,000 Daltons. As noted by Jordan, this permits free passage of steroid hormones and many nutrients, but not of the immunoglobulins. The bag was preferably tubular in form with a diameter of 4 mm or less, so as to assure easy diffusion of nutrients.
Jordan taught that this artificial gland could be implanted into the body in a manner so as to be in contact with the bloodstream, the artificial gland taking over the function of the natural gland, and the body regulating its activity and supplying it with nutrients.
Like Jordan's artificial gland, my intravascular artificial gland allows hormones to be supplied to the body under metabolic control and without continual injections to maintain the hormone supply. However, my gland is more suitable for prolonged use. If cells in Jordan's artificial gland die, or lose their secretory function, there is no ready means of replacing them. Nor is there any convenient method for eradicating an infectious agent which lodges itself in the gland, other than systemic treatment. Additionally, the cord with which Jordan fastens his bag may loosen in the harsh chemical environment of the bloodstream, thereby exposing the tissue to immunological attack.
Jordan's artificial gland is also vulnerable to mechanical strains which would damage the gland cells or rupture the container. While it may be implaced in the bone marrow as a protective measure, this might occasion some discomfort for the patient and might interfere with bone growth. The protective shield suggested by Jordan as an alternative might be dislodged by heavy physical exertion.
Lim, U.S. Pat. No. 4,391,909 teaches encapsulating living tissue in semipermeable microcapsules without impairing viability and injecting these microcapsules into a patient. While the capsules may be engineered to have a predetermined life, it is not possible to decide, after injection, to cease production of the substance secreted by the encapsulated tissue based on observation of the patient's clinical signs. (See also Seften, U.S. Pat. No. 4,353,888).
Matsumura, U.S. Pat. No. 3,734,851 descries a dialysis device in which liver cells are held within semipermeable membranes. Blood is extracted from the body and passed over the membranes. Metabolites pass from the liver cells to the blood, and enter the body when the blood is returned to the patient. While the cells are readily accessible, the need for extracorporeal processing tends to limit use of the device.
Berguer, U.S. Pat. No. 4,309,776 describes an islet cell culture device designed for implantation either as a "button" in the wall of a blood vessel or as a "sieve" in an arteriovenous fistula. The device has a chamber 12 and a tube 14 whereby cells may be injected into the chamber. The chamber has a semipermeable wall 18. The chamber, once implanted, cannot be readily repositioned, and there is no means for withdrawing dead cells.
Isono, U.S. Pat. No. 4,588,407 describes an extracorporeal artificial organ, with a preferred coating on the parts in contact with body fluid.
Indwelling catheters have frequently been used to deliver drugs to patients over prolonged periods. (See Marlon, U.S. Pat. No. 4,432,752; Pevsner, U.S. Pat. No. 4,509,523; Gordon, U.S. Pat. No. 4,531,936; Yates, U.S. Pat. No. 4,531,937). However, the adaptation of a catheter for intravascular organ, tissue or cell culture is novel.